Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the beneficial or harmful effects of antibiotic prophylaxis for patients submitted to elective laparoscopic cholecystectomy.
Background
Cholecystectomy is the universally accepted method to manage symptomatic, uncomplicated cholelithiasis and other benign gallbladder diseases, because it cures the disease and has low morbidity and mortality rates. Cholelithiasis is one of the most common abdominal diseases of adults (Bowen 1992; Angelico 1997). Although many patients are not symptomatic and gallbladder stones are an incidental finding during an ultrasonography, the largest number of patients have digestive complaints that compel to start a treatment. Furthermore, biliary dyskinesia and gallbladder polyps, although less frequent, are indications of elective cholecystectomy too.
The most frequent surgical complication in patients submitted to cholecystectomy is surgical site infection. Surgical site infections have been reported in 10% to 23% of patients operated on. Surgical site infections increase length of stay and decrease the quality of life (Richards 2003).
Since the 1960s, antibiotic prophylaxis has been stated as the best intervention to prevent surgical site infection in elective surgery. Antibiotic prophylaxis includes the preoperative administration of a wide spectrum antibiotics against the most frequent bacteria involved in surgical site infections, trying to get high tissue levels of the antibiotic at the surgical wound to avoid colonization and growing of microorganisms (Barie 2000; Weed 2003).
It is accepted that antibiotic prophylaxis must be administered in all surgical procedures classified as clean‐contaminated or in selected cases of clean procedures. Cholecystectomy is included in the clean‐contaminated category on the basis that the biliary tract is entered without significant spillage during the procedure.
Some randomised clinical trials have shown the beneficial and harmful effects of antibiotic prophylaxis in open cholecystectomy in decreasing the rate of surgical site infection (Jewesson 1996; Lippert 1998; Agrawal 1999).
Since 1985, with the original description of laparoscopic cholecystectomy, surgical treatment of benign gallbladder diseases, especially cholelithiasis, underwent a dramatic change. Development of minimally invasive surgery for intraabdominal diseases showed a decrease in length of stay, costs, postoperative pain, and an increase in quality of life of patients operated on (Barkun 1992; Berggren 1994; McMahon 1994; Majeed 1996). Although this new surgical method diminished the length and manipulation of surgical wound, antibiotic prophylaxis use did not change. Recent clinical trials have reevaluated the usefulness of antibiotic prophylaxis in laparoscopic cholecystectomy (Illig 1997; Higgins 1999; Harling 2000; Tocchi 2000; Mahatharadol 2001).
We were not able to find any meta‐analysis or systematic review investigating the beneficial and harmful effects of antibiotics when used as prophylaxis of surgical site infection in patients submitted to elective laparoscopic cholecystectomy.
Objectives
To assess the beneficial or harmful effects of antibiotic prophylaxis for patients submitted to elective laparoscopic cholecystectomy.
Methods
Criteria for considering studies for this review
Types of studies
All randomised clinical trials comparing the use of prophylactic antibiotics versus no antibiotics or placebo in patients submitted to elective laparoscopic cholecystectomy because of cholelithiasis without acute cholecystitis or other benign, non‐acute inflammatory disease of the gallbladder, confirmed by ultrasonography or other imaging procedures.
Trials will be included irrespectively of number of patients randomised, database registry, and language of the article. Quasi‐randomised studies will be excluded, but data on adverse effects, if available, will be recorded.
Types of participants
Adult patients (more than 17 years old) with preoperative clinical diagnosis of cholelithiasis without acute cholecystitis or other benign, non‐acute inflammatory disease of the gallbladder. Jaundiced patients will be excluded.
Types of interventions
Antibiotic prophylaxis versus no antibiotic or placebo, administered intravenously or orally prior to surgery.
Types of outcome measures
Primary outcome measure
(1) Surgical site infection defined according to the the Centers for Disease Control and Prevention (CDC)'s classification (Mangram 1999), recorded as 'number of complications' , 'types of complications', and 'number of patients with at least one complication'.
Secondary outcome measures
(2) Extra‐abdominal infections defined according to the CDC's classification (Mangram 1999)
(3) All‐cause mortality.
(4) Adverse events.
(5) Quality of life.
All outcome measures will be confined to within hospitalisation, 30 days after discharge, and at maximal follow up.
Search methods for identification of studies
We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4, 2004), The National Library of Medicine (PubMed) (1985 to September 2004), The Intelligent Gateway to Biomedical & Pharmacological Information (EMBASE) (1985 to November 2004), The LatinAmerican and Caribbean Health Sciences Library (LILACS) (1985 to November 2004), and Science Citation Index Expanded (SCI‐EXPANDED) (1985 to November 2004). Searches will not be performed before 1985, as laparoscopic cholecystectomy was only conducted from 1985 onwards.
The search strategy will identify studies in all languages and when necessary, non‐English language papers will be translated so that they could be fully assessed for potential inclusion in the review. The search strategy for the review will be constructed by using a combination of MESH subject headings and text words, relating to the use of prophylactic antibiotics in laparoscopic cholecystectomy for cholelithiasis (Appendix 1).
We will write to authors of included trials for information on any published, unpublished, and ongoing trials. We will also check the reference lists of all the identified trials for more relevant trials. Published abstracts from the conference proceedings from the American Digestive Disease Week (DDW) published in Gastroenterology and the United European Gastroenterology Week (UEGW) published in Gut will also be handsearched. In addition, experts in the field and pharmaceutical companies will be contacted and asked to provide details of outstanding clinical trials or any relevant unpublished materials. The international societies of minimally invasive surgery (European and American Laparoscopic Surgery Society) and the international gastrointestinal surgery societies (Gastrointestinal Surgery Society) will also be contacted and asked to provide information on any unpublished studies.
Data collection and analysis
We will conduct the review according to the present protocol and the recommendations by The Cochrane Reviewers' Handbook (Alderson 2004).
AS and EV will extract the data, and a consensus will be sought in case of disagreements. AS will perform the statistical analysis. We will list identified trials and will make an evaluation whether the trials fulfil the inclusion criteria. We will also list the excluded trials with the reasons for exclusion.
Assessment of methodological quality
We will define the methodological quality as the confidence that the design and report restrict bias in the intervention comparison (Moher 1998; Kjaergard 2001). Due to the risk of overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001), we will assess the influence of methodological quality.
Generation of the allocation sequence
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Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
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Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.
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Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and will be excluded from the present review when assessing beneficial effects.
Allocation concealment
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Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, or sealed envelopes.
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Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
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Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised.
Blinding (or masking)
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Adequate, if the trial was described as double blind and the method of blinding was described.
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Unclear, if the trial was described as double blind, but the method of blinding was not described.
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Not performed, if there was no blinding at all.
Follow‐up
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Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
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Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
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Inadequate, if the number or reasons for dropouts and withdrawals were not described.
Extraction of data
We will record the inclusion and exclusion criteria in each trial that fulfills our criteria for inclusion.
The following details on methods will be extracted:
(1) Use of prophylactic antibiotics: Prophylaxis is defined as the use of antibiotic before the infection occurs and prior to surgery.
(2) Number of laparoscopic cholecystectomies converted to open cholecystectomies.
The following data on randomisation and blinding procedure will be extracted:
(1) Number of randomised patients.
(2) Number of patients not randomised and reasons for non‐randomisation.
(3) Exclusion after randomisation.
(4) Drop‐outs.
(5) Blinding of patients and observers.
(6) 'Intention‐to‐treat' analysis.
(7) Internal validity.
Data on septic and non‐septic abdominal complications (surgical site infections, biliary tract injury, biliary leakage), extra‐abdominal complications, and number of deaths will be extracted if present.
Statistics
The statistical package (RevMan Analyses 4.2) provided by The Cochrane Collaboration will be used. For dichotomous outcomes, the impact of the intervention will be expressed as an odds ratio together with 95% confidence interval. In the analysis of continuous variables, generally authors present their results in medians with ranges. However, for the analysis of data in a meta‐analysis, means with their corresponding standard deviations are needed to calculate weighted or standardized mean differences with 95% confidence intervals. Using means from all trials would ignore non‐Gaussian distribution. On the other hand using medians to calculate average data would be incorrect. We recognise this problem of data analysis and we will choose the best appropriate method to deal with this dilemma, ie, asking for original data from the individual trials. We will use both a random‐effects model and a fixed‐effect model. In case of discrepancy between the two models (eg, one giving a significant intervention effect, the other no significant intervention effect) we will report both results, otherwise we will report only the results from the fixed model.
Heterogeneity
The chi‐square test for heterogeneity will be used to provide an indication of between‐study heterogeneity. In addition, the degree of heterogeneity observed in the results will be quantified using the I2 statistic, which can be interpreted as the percentage of variation observed between the studies attributable to between‐study differences rather than sampling error (chance).
Intention‐to‐treat analyses
Regarding the primary outcome measure we will include patients with incomplete or missing data in the sensitivity analyses by imputing them according to the following scenario. Carry forward analysis: if patients had missing outcome data, we would use the last reported observed response ('carry forward') in the nominator and would include all randomised participants in the denominator.
Subgroup analyses
We will perform a subgroup analysis in order to compare the intervention effect in trials with high methodological quality (ie, trials with adequate generation of the allocation sequence, allocation concealment, and blinding) to that of trials with low methodological quality (ie, trials not having one or more adequate component). We will also perform subgroup analyses according to type of patients included in the trials as well as type of antibiotic/antibiotics tested in the trials. Further, we will explore causes of heterogeneity (defined as the presence of statistical heterogeneity by chi‐squared test with significance set at P‐value less than 0.10 and measure the quantities of heterogeneity by I2 (Higgins 2002) by comparing different groups of trials stratified according to patient risk factors, level of experience of the surgeon, and other factors that may explain heterogeneity.
Bias detection
We will use funnel plot to provide a visual assessment of whether treatment estimates are associated with study size. The detection of publication bias and other biases (Egger 1997; Macaskill 2001) varies with the magnitude of the treatment effect, the distribution of study size, and whether a one‐ or two‐tailed test is used (Macaskill 2001). We will use two tests to assess funnel plot asymmetry, adjusted rank correlation test (Begg 1994) and regression asymmetry test (Egger 1997).
